Purpose/Objective(s) For human papilloma virus related (HPV+ve) primary oropharyngeal squamous cell carcinoma (OPC), blood tests can quantify circulating cell free tumor tissue modified viral (TTMV)-HPV DNA at diagnosis and after treatment during follow-up. The purpose of this study is to investigate the correlation between baseline tumor volume and pre-treatment TTMV-HPV DNA titers for HPV+ve OPC. Materials/Methods We queried our institutional database to identify non-metastatic HPV+ve OPC patients with available pre-treatment TTMV-HPV 16 DNA scores. All patients have the gross tumor volume (GTV) for the primary (GTVp), involved lymph nodes (GTVn) and total tumor volume (TTV = GTVp + GTVn) calculated in cc on the contrast enhanced radiation treatment planning CT-scan. We excluded patients with negative and intermediate TTMV-HPV 16 pre-treatment scores, those with N0 OPC and those with HPV+ve nodes with no detected primary. Spearman's rho correlation (two tailed, significance at the 0.01 level) was performed to determine correlations among all tumor volumes and the pretreatment TTMV-HPV 16 DNA scores. Results We identified 29 patients who met our inclusion criteria: 90% were males, 89.6% white, median age was 64 (range = 42-81) years, 24% were current smokers and 20.1% were former smokers with median pack-years of 22.5 (range = 1.8-61) and 48.3% reported a history of alcohol use. More than half of the patients had base of the tongue location (51.7%) followed by tonsil (41.4%), with T1, T2, T3 and T4 tumors detected in 27.6%, 27.6%, 27.6% and 17.2%, whereas 38% and 62% had N2 and N1 disease, respectively. Mean (standard deviation) GTVp, GTVn, and TTV were 30.2 ± 30.9, 28.3 ± 30.4, and 58.5 ± 47.2 cc, respectively and median (range) of TTMV-HPV 16 DNA score was 483 (19-126009) fragments/ml plasma. Spearman's rho showed a significant positive moderate correlation with both GTVn and TTV and TTMV-HPV 16 DNA scores (See Table 1 below). Statistically significant correlation was not observed with GTVp. Conclusion Nodal tumor volume and total tumor volume showed moderate positive correlation with pretreatment TTMV-HPV-16 DNA titers for HPV+ve OPC. *. Correlation is significant at the 0.05 level (2-tailed).

PURPOSE:To analyze clinical toxicity and quality-of-life (QOL) outcomes among patients with stage I non-small cell lung cancer (NSCLC) after stereotactic body radiation therapy (SBRT) as a function of radiation dose and volume parameters. METHODS AND MATERIALS:In this institutional review board-approved study, 55 patients with stage I NSCLC who received SBRT (12 Gy × 4) and completed QOL forms were analyzed. Clinical symptoms and QOL outcomes were measured at baseline and at 3, 6, 12, 18, 24, and 36 months after SBRT. Clinical toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Lung-Trial Outcome Index (FACT-L-TOI) instrument. Dosimetric parameters including the mean lung radiation dose and the volume of normal lung receiving greater than 5, 10, 13, or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student t tests and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxic effects. The Kaplan-Meier method was used to estimate rates of local control (LC), disease-free survival (DFS), and overall survival (OS). RESULTS:With a median follow-up of 24 months, the 3-year LC, DFS, and OS were 93%, 65%, and 84%, respectively, with a 5.5% rate of grade-3 toxic effects and no grade 4 or 5 toxic effects. Clinically meaningful declines in patient-reported QOL (FACT-L-TOI, lung cancer subscale, physical well-being, and/or functional well-being) posttreatment significantly correlated with increased dosimetric parameters such as V10, V13, and V20. CONCLUSION:Although lung SBRT was associated with excellent LC and minimal clinical toxic effects for early-stage NSCLC, clinically meaningful declines in QOL were significantly correlated with increasing lung dose and volume parameters.

Purpose:To investigate correlation of normal lung CT density changes with dose accuracy and outcome after SBRT for patients with early stage lung cancer.Methods:Dose distributions for patients originally planned and treated using a 1‐D pencil beam‐based (PB‐1D) dose algorithm were retrospectively recomputed using algorithms: 3‐D pencil beam (PB‐3D), and model‐basedMethods:AAA, Acuros XB (AXB), and Monte Carlo (MC). Prescription dose was 12 Gy × 4 fractions. Planning CT images were rigidly registered to the followup CT datasets at 6–9 months after treatment. Corresponding dose distributions were mapped from the planning to followup CT images. Following the method of Palma et al .(1–2), Hounsfield Unit (HU) changes in lung density in individual, 5 Gy, dose bins from 5–45 Gy were assessed in the peri‐tumor region, defined as a uniform, 3 cm expansion around the ITV(1).Results:There is a 10–15% displacement of the high dose region (40–45 Gy) with the model‐based algorithms, relative to the PB method, due to the electron scattering of dose away from the tumor into normal lung tissue (Fig.1). Consequently, the high‐dose lung region falls within the 40–45 Gy dose range, causing an increase in HU change in this region, as predicted by model‐based algorithms (Fig.2). The patient with the highest HU change (∼110) had mild radiation pneumonitis, and the patient with HU change of ∼80–90 had shortness of breath. No evidence of pneumonitis was observed for the 3 patients with smaller CT density changes (<50 HU). Changes in CT densities, and dose‐response correlation, as computed with model‐based algorithms, are in excellent agreement with the findings of Palma et al. (1–2).Conclusion:Dose computed with PB (1D or 3D) algorithms was poorly correlated with clinically relevant CT density changes, as opposed to model‐based algorithms. A larger cohort of patients is needed to confirm these results.This work was supported in part by a grant from Varian Medical Systems, Palo Alto, CA

Stereotactic body radiation therapy (SBRT) is an appropriate treatment option for patients with stage I non-small cell lung cancer (NSCLC) who are not surgical candidates. As these patients often present with significant co-morbidities, quality of life (QOL) outcomes are especially important. To use a validated patient reported quality of life (QOL) assessment tool to measure clinical toxicity and patient reported quality of life (QOL) outcomes up to 36 months after SBRT in stage I NSCLC patients based on pre-treatment dosimetric parameters and tumor volumes. Fifty-six stage I NSCLC patients treated with SBRT (12 Gy x 4) were prospectively monitored for symptoms including cough, dyspnea, fatigue, and pneumonitis. Symptoms were measured at baseline (before treatment), immediately after treatment and 3, 6, 12, 18, 24, and 36 months post-treatment. Toxicity was graded from zero to five following the Charlson comorbidity and toxicity index. Quality of life was determined using the previously-validated Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) Lung questionnaire which incorporated three subscale endpoints: lung subscale (LSC), physical well-being (PWB) and functional well-being (FWB). Dosimetric parameters, including the mean lung radiation dose (MLD), and the volume of normal lung receiving at least 5, 10, 13 or 20 Gy (V5, V10, V13, and V20) were obtained from the treatment plan. Pearson correlation and student t-test analyses were used to measure correlations and distinguish between lung metrics with QOL and clinical toxicities. SBRT produced minimal toxicities. QOL (TOI, LSC, PWB, or FWB) at 3, 6, 12 and 24 months post-treatment were significantly correlated with V5, V10, V13, V20, or MLD. Radiation pneumonitis showed mild positive but statistically significant (P < 0.05) correlation with V20. Moreover, FWB at 3 months showed mild negative correlation with dyspnea. Lung SBRT treatment for patients with NSCLC, using a 12 Gy x 4 dose regimen, was well tolerated with minimal toxicity observed. A validated patient related quality of life assessment tool was used to identify the dosimetric parameters most crucial for treatment planning. Further follow-up is recommended.

Purpose: To describe a custom-built, web-based MR Quality Control QC database, and to make a preliminary assessment of its impact on the Quality Assurance QA process in a large U.S. hospital.Methods: The MR QC database was built with Microsoft Access 2010 and published on a Microsoft Sharepoint website owned and maintained by the authors' institution.Authorized users can access the database remotely with mainstream web browsers.QC technologists were granted access to add, review, and print daily and weekly QC records.Qualified medical physicists (QMPs) were granted additional access to edit, review, and approve existing QC records, and to change tolerance limits.A macro was utilized to conduct an automatic weekly review of QC status, and to email the results to a QMP.This web-based QC database was implemented on five clinical MRIs at the authors' institution.Weekly ACR QC findings within five months before and after implementation were compared.Results: Retrospective review of the conventional QC records before implementation revealed 26 QC issues.After the adoption of the new web database, the number of QC issues reduced by 38% to 16.Since only a small fraction of these issues were reported at the time of occurrence, the web-based database permitted the QMPs to more quickly identify a QC issue (before/after: 7.6 ± 7.5/ 1 ± 0 weeks, P = 0.0002).Among the 26 QC issues occurred before the implementation, 8 issues (31%) would have been handled differently had they been identified earlier.The time to corrective actions was also found to be slightly shorter with the web-based system, although the difference is not statistically significant (before/after: 3.2 ± 2.7/1.7 ± 2.1 weeks, P = 0.3).Conclusion: The web-based QC database provides a positive impact on our MR QA process.It enables early detection and facilitates resolution of potential issues that may affect the quality of clinical MRI studies.

BACKGROUND:Personalized medicine for patients receiving radiation therapy remains an elusive goal due, in part, to the limits in our understanding of the underlying mechanisms governing tumor response to radiation. The purpose of this study was to develop a kinetic model, in the context of locally advanced lung cancer, connecting cancer cell subpopulations with tumor volumes measured during the course of radiation treatment for understanding treatment outcome for individual patients.METHODS:The kinetic model consists of three cell compartments: cancer stem-like cells (CSCs), non-stem tumor cells (TCs) and dead cells (DCs). A set of ordinary differential equations were developed to describe the time evolution of each compartment, and the analytic solution of these equations was iterated to be aligned with the day-to-day tumor volume changes during the course of radiation treatment. A least squares fitting method was used to estimate the parameters of the model that include the proportion of CSCs and their radio-sensitivities. This model was applied to five patients with stage III lung cancer, and tumor volumes were measured from 33 cone-beam computed tomography (CBCT) images for each of these patients. The analytical solution of these differential equations was compared with numerically simulated results.RESULTS:For the five patients with late stage lung cancer, the derived proportions of CSCs are 0.3 on average, the average probability of the symmetry division is 0.057 and the average surviving fractions of CSCs is 0.967, respectively. The derived parameters are comparable to the results from literature and our experiments. The preliminary results suggest that the CSC self-renewal rate is relatively small, compared to the proportion of CSCs for locally advanced lung cancers.CONCLUSIONS:A novel mathematical model has been developed to connect the population of cancer stem-like cells with tumor volumes measured from a sequence of CBCT images. This model may help improve our understanding of tumor response to radiation therapy, and is valuable for development of new treatment regimens for patients with locally advanced lung cancer.

Purpose:To correlate dose distributions computed using six algorithms for recurrent early stage non‐small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT), with outcome (local failure).Methods:Of 270 NSCLC patients treated with 12Gyx4, 20 were found to have local recurrence prior to the 2‐year time point. These patients were originally planned with 1‐D pencil beam (1‐D PB) algorithm. 4D imaging was performed to manage tumor motion. Regions of local failures were determined from follow‐up PET‐CT scans. Follow‐up CT images were rigidly fused to the planning CT (pCT), and recurrent tumor volumes (Vrecur) were mapped to the pCT. Dose was recomputed, retrospectively, using five algorithms: 3‐D PB, collapsed cone convolution (CCC), anisotropic analytical algorithm (AAA), AcurosXB, and Monte Carlo (MC). Tumor control probability (TCP) was computed using the Marsden model (1,2). Patterns of failure were classified as central, in‐field, marginal, and distant for Vrecur ≥95% of prescribed dose, 95–80%, 80–20%, and ≤20%, respectively (3).Results:Average PTV D95 (dose covering 95% of the PTV) for 3‐D PB, CCC, AAA, AcurosXB, and MC relative to 1‐D PB were 95.3±2.1%, 84.1±7.5%, 84.9±5.7%, 86.3±6.0%, and 85.1±7.0%, respectively. TCP values for 1‐D PB, 3‐D PB, CCC, AAA, AcurosXB, and MC were 98.5±1.2%, 95.7±3.0, 79.6±16.1%, 79.7±16.5%, 81.1±17.5%, and 78.1±20%, respectively. Patterns of local failures were similar for 1‐D and 3D PB plans, which predicted that the majority of failures occur in centraldistal regions, with only ∼15% occurring distantly. However, with convolution/superposition and MC type algorithms, the majority of failures (65%) were predicted to be distant, consistent with the literature.Conclusion:Based on MC and convolution/superposition type algorithms, average PTV D95 and TCP were ∼15% lower than the planned 1‐D PB dose calculation. Patterns of failure results suggest that MC and convolution/superposition type algorithms predict different outcomes for patterns of failure relative to PB algorithms.Work supported in part by Varian Medical Systems, Palo Alto, CA

Purpose:To determine in a prospective study, the correlation between radiation dose/volume, clinical toxicities and patient‐reported, quality of life (QOL) resulting from lung SBRT.Methods:For 106 non‐small cell lung cancer (NSCLC) patients receiving SBRT (12 Gy × 4), symptoms including cough, dyspnea, fatigue and pneumonitis were measured at baseline (before treatment), after treatment and 3, 6, and 12 months post‐treatment. Toxicity was graded from zero to five. Dosimetric parameters such as the MLD, D10%, D20%, and lung subvolumes (V10 and V20) were obtained from the treatment plan. Dosimetric parameters and number of patients demonstrating toxicity ≥ grade 2 were tabulated. Linear regression analysis was used to calculate correlations between MLD and D10, D20, V10 and V20.Results:The percentages of patients with > grade 2 pneumonitis, fatigue, cough, and dyspnea over 3 to 12 months increased from 0.0% to 3.5%, 3.2% to 10.5%, 4.3% to 8.3%, and 10.8% to 18.8%, respectively. Computed dose indices D10%, D20% were 7.9±4.8 Gy and 3.0±2.3 Gy, respectively. MLD ranged from 0.34 Gy up to 9.9 Gy with overall average 3.0±1.7 Gy. The averages of the subvolumes V10 and V20 were respectively 8.9±5.3% and 3.0±2.4%. The linear regression analysis showed that V10 and D10 demonstrated the strongest correlation to MLD; R2= 0.92 and 0.87, respectively. V20, and D20 were also strongly correlated with MLD; R2 = 0.81 and 0.84 respectively. A correlation was also found to exist between MLD > 2 Gy and ≥ grade 2 cough and dyspnea. Subvolume values for 2Gy MLD were 5.3% for V10 and 2% for V20.Conclusion:Dosimetric indices: MLD ≥ 2Gy, D10 ≥ 5Gy and V10 ≥ 5% of the total lung volume were predictive of > grade 2 cough and dyspnea QOL data. The QOL results are a novel component of this work.acknowledgement of the Varian grant support.

To investigate the correlation between pathology and Raman spectroscopic signal from tumor and normal tissue after radiation exposure in an animal model. Nineteen female Balb/C mice were investigated. Five mice were used as “unirradiated normal lung” controls. 14 mice were implanted with 4T1 breast cancer cells (∼1/2 million) to their right flanks. 4T1 breast cancer cells injected intramuscularly metastasize to the lungs by day 14. Among these 14 mice, 5 were “unirradiated tumor” controls. After day 14, the remaining 9 mice received radiation in a single fraction of 12 or 18 Gy to the left lung with 6MV photons. One to two days after radiation, lungs were removed, snap frozen, and stored in a -800C freezer. Lung specimens were sectioned using a cryostat-microtome for pathologic evaluations and Raman measurements. Principal component analysis (PCA) and discriminant function analysis (DFA) were used to analyze the data. Table 1 shows the results of the PCA/DFA analyses relative to pathologic scoring as well as the number of Raman spectra recorded from each group. A total of 675 Raman spectra were collected as follows: 126 (unirradiated tumors), 108 (tumors receiving 12 Gyx1), 130 (tumors receiving 18 Gyx1), 204 (irradiated normal lung tissues (bearing tumors)), with 91 of these normal lung spectra from 12 Gyx1, and 113 from 18 Gyx1; 107 (unirradiated normal lung tissues). Raman spectroscopy was able to differentiate unirradiated tumor and unirradiated normal tissues with 100% sensitivity relative to pathologic scoring. The classification results showed an overall accuracy of 81.9% relative to pathology evaluation in identifying unirradiated tumor vs. irradiated tumors with 12 or 18 Gy. Similarly, Raman spectroscopy was able to differentiate unirradiated normal from irradiated normal lung tissues with a specificity of 87.9%. Raman spectroscopy is shown to identify irradiated vs. unirradiated lung tumors and normal lung radiation response with high sensitivity and specificity relative to pathologic scoring. This suggests a role for the Raman method to diagnosis the presence of tumor and in analyzing post-radiation patient tissues to assess response.Poster Viewing Abstracts 3496; Table 1A summary of PCA/DFA classification of each group relative to pathological evaluationDescriptionGroupNo. of Raman spectraClassification relative to pathologic scoringNormal vs. TumorUnirradiated normal lung107100%Unirradiated lung tumor126100%Unirradiated vs. irradiated normal lungUnirradiated lung tumor12678.512 Gy irradiated lung tumor10885.718 Gy irradiated lung tumor13081.4Unirradiated vs. irradiated normal lungUnirradiated normal lung10787.912 Gy irradiated normal lung9187.918 Gy irradiated normal lung11383.2 Open table in a new tab

BACKGROUND:The objective of this study is to establish Raman signatures from pure cultures of different Candida species using Raman Spectroscopy (RS) and use these signatures for rapid identification of unknown Candida species.METHODS:Pure cultures of five Candida species were evaluated using RS to build a limited signature library. 'Raman Processing' (RP) software was used for Principal Component Analysis (PCA) and Differential Functional Analysis (DFA).RESULTS:Eleven principal components described at least 95% variance in the spectra. Raman signatures from these known Candida species were able to identify the species of unknown Candida cultures with 100% accuracy.CONCLUSION:Raman spectroscopy can improve early identification of Candida species and may facilitate early optimal antifungal therapy.

Purpose: Stereotactic body radiotherapy (SBRT) is commonly used to treat early stage lung tumors. This study was designed to evaluate associations between dose, volume and clinical outcomes including analysis of both clinical toxicity scores and quality of life (QOL) data for non-small cell lung cancer patients treated with SBRT. Preliminary results are presented. Methods: Sixty-seven NSCLC patients, 46 primarily with early stage, and 21 with recurrent disease were treated with dose regimens consisting mainly of 12 Gy × 4 fractions, and 3 or 5 fractions at lower dose, for patients with recurrent disease (Table 1). Follow-up data is being collected at baseline, after treatment and at 3, 6, 12, 18 and 24 months post-treatment. Clinical follow-up data acquired to date was assessed using the Charlson Comorbidity Clinical and Toxicity Scoring forms. QOL data was evaluated using the EQ-5D, and FACT-TOI validated surveys. All outcomes surveys are collected within an “in-house” developed outcomes database. Results: The median follow-up was 3.5±0.8 months. Mean lung doses (MLD) were converted to BED-2 Gy using the linear-quadratic model with an alpha/beta=3.0. Average MLD was 3.7+3.1 Gy (range: 0.4–20.9 Gy). The percentages of patients with > grade 2 cough, dyspnea and fatigue were 13.3, 17.0, 6.3%, respectively. Preliminary analyses (at 3 months after SBRT) show a mild correlation between MLD > 2 Gy and > grade 2 cough (borderline significant) and dyspnea (significant, p<0.05). One patient was observed with a grade 3 cough. Given the short follow-up, tumor control is not yet assessable. Conclusion: The SBRT dose fractionation regimen of 12 Gy × 4 was well tolerated at early time points. Additional follow-up is required to assess the long-term clinical outcome efficacy and toxicity profiles of the dose regimen.